When physicians treat patients with a drug, significant clinical variability is often observed. This variability is manifested in both the frequency of response to treatment, as well as the frequency and nature of possible adverse “side effects.” Because of this well documented heterogeneity in clinical responses to drug treatment, physicians often must empirically adjust clinical dosages of the therapeutic agents used, or discontinue the use of a drug and switch to an alternative treatment to successfully treat a given medical indication. This variability in response to pharmacotherapy results in significantly increased health care costs, and delays in successful treatment. Clearly, there exists a need to identify patients who will respond positively to a particular medication, as well as those who are more prone to adverse side effects.
Similarly, the susceptibility to a given disease, as well as the rate of a disease's clinical progression varies across human populations. This is particularly true for human diseases where a complex interaction of genetics and environment are necessary for disease manifestation. In some individuals the clinical course of disease may be very benign, abrogating the need for intensive treatment that may expose that individual to adverse side effects. Conversely, the clinical course may be very severe, emphasizing the risk benefit ratio for aggressive and early intervention in disease treatment. Consequently, it is important to identify patients who exhibit increased risk of disease, or to identify individuals who will display either a severe or benign clinical course, as this will provide valuable information to clinicians to help tailor therapeutic decisions, and optimize the diagnosis and treatment of human disease.
Variability in clinical response to therapeutic drugs is determined in large part by genetic heterogeneity across human populations. For any given therapeutic drug, inter-individual variation in factors such as absorption, distribution, drug/target interactions, and elimination can all create variability in treatment response. Processes such as absorption, distribution, and elimination can all be easily assessed in the clinical setting by determining serum levels of a given therapeutic drug. However, variability in drug/target molecules has yet to be routinely considered in the clinical variability of drug treatment responses.
Similarly, variability in disease progression and susceptibility is determined in large part by genetic heterogeneity across human populations. Particular genes may be directly pathophysiological in a particular disease state, or may serve a modulatory role, where alterations in gene function may be modifying factors in the clinical manifestation and course of an individual's illness. The knowledge that a particular genetic variant is functionally altered can enable that genetic variant to be a marker for disease susceptibility and progression, even in a setting where the precise role of that gene and gene product are currently not understood.
Drug target genes, specifically the large gene families of receptor proteins (GPCR's) that transduce information by coupling to guanine nucleotide binding proteins, not only mediate the physiological effects of exogenously administered pharmaceutical agents, they also sub-serve critical roles in a diverse set of physiological processes. As such, genetic variants of these genes, in particular those variants that alter receptor function, are candidates to not only determine clinical responses to therapeutic drugs, but to modify disease susceptibility and progression.
Most mammalian genes, including drug target genes, are highly polymorphic across human populations. The most common form of polymorphism is the single nucleotide polymorphism (SNP), where a single nucleotide of DNA differs between individuals in a population. SNPs occur within both intergenic sequences, as well as in regulatory, and both exonic and intronic regions of human genes. In addition, any given individual may harbor multiple SNPs within a given genomic region, resulting in a multitude of different possible combinations of SNPs termed a haplotype. Of those SNPs that occur within exonic regions of genes, some are termed synonymous, in that they do not change the amino acid sequence of the resulting protein, and are unlikely to affect protein function. However, some of these coding region SNP's are non-synonymous (nscSNP), in that the single base change in the DNA does change the amino acid at that corresponding position in the protein. Significantly, SNPs are surprisingly frequent across the human genome (current estimates suggest 10 million total SNPs), and although most of these SNPs will have little or no functional consequences, others may affect protein function. Therefore, the identification of SNPs that alter protein function provides the genetic basis of the biological and pharmacological differences between individuals with respect to pharmacological treatment outcomes and disease susceptibility and progression. In addition, identification of functionally altered polymorphic variants of a given drug target gene can be generalized to define the genetic haplotypes associated with altered clinical outcomes.